Four major types of striatal projection neurons have been identified in the basal ganglia: (1) striatonigral neurons contain substance P (SP, dynorphin (DYN) and GABA; (2) striatonigral neurons containing enkephalin (ENK) and GABA; (3) striatopallidal neurons containing SP, DYN and GABA; and (4) striatopallidal neurons containing ENK and GABA. The proposed studies will determine the morphological difference between these neuronal populations in terms of their outputs, local circuit connections and major inputs, thereby shedding light on the neural substrate underlying the functional differences between these striatal populations. The studies will be conducted in pigeons, in whom SP+ and ENK+ neurons can be extensively labeled immunohistochemically and in whom striatonigral and striatopallidal neurons can be distinguished by their differential localization in the striatum. Studies on the outputs of these four neuronal populations will seek to determine the identities of the target neurons of each, using double-and triple-label LM and EM immunohistochemical techniques, with specific types of nigral and pallidal target neurons being retrogradely labeled from their target areas or labeled immunohistochemically. Studies on the local circuit connections of striatal projection neurons will use EM immunohistochemical double-label techniques to determine the pattern of intrastriatal connectivity among these types of neurons, as well as the pattern of input to these types of neurons from cholinergic striatal interneurons. Finally, LM and EM immunohistochemical double-label techniques will be used to examine the nigral dopaminergic and corticostriatal inputs to the four major types of striatal projection neurons. Nigral inputs will be visualized using anti-tyrosine hydroxylase immunohistochemistry and corticostriatal inputs will be visualized using PHAL anterograde labeling. All studies on the intrastriatal and extrastriatal inputs to the four types of striatal projection neurons will seek to determine if specific types of inputs synapse and/or are differentially distributed on the different types of neurons. To further explore how the four major populations of striatal projection neurons are differentially controlled by their inputs, immunofluorescence double-label techniques will be used to determine the localization of D1 and D2 dopamine receptors and muscarinic cholinergic receptors (using immunohistochemical markers of these receptors) on the four types of striatal projection neurons. These studies will aid in understanding the nature and anatomical basis of the functional differences between the different types of striatal projection neurons. Since these populations are affected in Huntington's disease and Parkinson's disease, the studies may aid in understanding the neural basis of such movement disorders and suggest novel therapeutic approaches.